Compositions and method for treating depression

ABSTRACT

The present invention describes the combination of a 5HT3-antagonist with pramipexole to reduce or eliminate the adverse effects associated with the use of pramipexole and to enable the use of high doses of pramipexole, useful for treating depressive disorders such as major depressive disorder.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 62/489,016, filed Apr. 24, 2017, the disclosure ofwhich is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention pertains to the field of the treatment ofdepression.

OBJECT OF THE INVENTION

The present invention concerns pharmaceutical combinations, includingfixed-dose combinations, comprising a 5HT3-antagonist and an effectivepramipexole dose, for the treatment of major depressive disorders.

Definitions

-   -   “CGI”: Clinical Global Impression.    -   “CNS”: Central Nervous System.    -   “IR”: Immediate Release of the active ingredient from a        composition.    -   “ER”: Extended Release of the active ingredient from a        composition.    -   “GI”: Gastro-Intestinal.    -   “AE(s)”: Adverse Effect(s).    -   “DSM-5”: Diagnostic and Statistical Manual of Mental Disorders,        5^(th) edition.    -   “I-IAMD”: Hamilton Depression Rating Scale.    -   “MADRS”: Montgomery and Asberg Depression Rating Scale.    -   “MDD”: Major Depressive Disorder.    -   “MAOIs”: Monoamine oxidase inhibitors.    -   “NIMH”: National Institute of Mental Health.    -   “PD”: Parkinson's Disease.    -   “Persistent depressive disorder”: also called dysthymia.    -   “PMDD”: Premenstrual Dysphoric Disorder.    -   “5HT3-antagonist”: an antagonist of the serotonin receptor        subtype-3, in the literature also referred to as a 5-HT3        receptor antagonist or a 5-HT3 receptor inhibitor.    -   “Effective daily dose of 5HT3-antagonist”: as used herein,        refers to a daily dose of said 5HT3-antagonist of from 1 μg to        300 mg.    -   “Effective dose/unit form of a 5HT3-antagonist” or “effective        dose per unit form of a 5HT3-antagonist”: an amount of said        5HT3-antagonist per unit form in the range of from 1 μg to 300        mg.    -   “Pramipexole”: the        (S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine,        as active principle including the free base and its        pharmaceutically acceptable salts and solvates, unless otherwise        specified.    -   “Effective daily dose of pramipexole” or “therapeutically        effective dose of pramipexole”: a daily pramipexole dose        equivalent to at least a pramipexole dihydrochloride monohydrate        approved daily dose for the symptomatic treatment of PD, this        effective daily dose including low daily doses used during the        titration period.    -   “Effective dose/unit form” or “effective dose per unit form”, in        reference to pramipexole: a pramipexole amount per unit form        equivalent to at least a pramipexole dihydrochloride monohydrate        amount per unit form approved for the symptomatic treatment of        PD, this amount including low amounts per unit form used during        the titration period.    -   “Salts or solvates thereof” or “salts and solvates thereof”,        with reference to any 5HT3-antagonist or to pramipexole: this        expression indicates that any salt of said pramipexole or said        5HT3-antagonist may be solvated with a solvent, normally water.    -   “SSRIs”: Selective serotonin reuptake inhibitors.    -   “NDRIs”: Norepinephrine-dopamine reuptake inhibitors.    -   “TCAs”: Tricyclic antidepressants.    -   “TTS”: Transdermal Therapeutic System.    -   “Depressive disorders”: include, but is not limited to, major        depressive disorder (MDD), persistent depressive disorder        (dysthymia), Bipolar depression, seasonal affective disorder        (SAD), psychotic depression, premenstrual dysphoric disorder        (PDD), peripartum (postpartum) depression, situational        depression, and atypical depression. The common feature of these        depressive disorders is the presence of sad, empty, or irritable        mood, accompanied by somatic and cognitive changes that        significantly affect the individual's capacity to function. The        difference among these disorders are issues of duration, timing        or presumed etiology. See Depressive Disorders, Diagnostic and        Statistical Manual of Mental Disorders, Fifth Edition,        dsm.psychiatryonline.org/doi/10.1176/appi.books.9780890425596.dsm04.

BACKGROUND OF THE INVENTION

Major depressive disorder (MDD), also referred to as depression orclinical depression, is a common but serious mood disorder associatedwith a significant burden, affecting around 16% of the population in theUS in their lifetime (reviewed in de Sousa et al, 2015). Depression isone of the most common mental disorders in the U.S. Current researchsuggests that depression is caused by a combination of genetic,biological, environmental, and psychological factors.

The estimated costs of MDD are around 83 billion US Dollars annually,due to many psychosocial factors including loss of workdays (reviewed inde Sousa et al, 2015). Estimates are that on average a depressed personloses 27.2 workdays per year (reviewed in de Sousa et al, 2015). Asignificant part of the burden corresponds to unsuccessful treatments.Remission of depressive symptoms is achieved in only one-third of theMDD patients after the first antidepressant trial (reviewed in de Sousaet al, 2015), and unsuccessful treatments contribute substantially tothe observed suffering and social costs of MDD.

Signs and symptoms of depression typically consist of the following:persistent sad, anxious, or “empty” mood; feelings of hopelessness orpessimism; irritability; feelings of guilt, worthlessness, orhelplessness; loss of interest or pleasure in hobbies and activities;decreased energy or fatigue; moving or talking more slowly; feelingrestless or having trouble sitting still; difficulty concentrating,remembering, or making decisions; difficulty sleeping, early-morningawakening, or oversleeping; appetite and/or weight changes; thoughts ofdeath or suicide, or suicide attempts; aches or pains, headaches,cramps, or digestive problems without a clear physical cause and/or thatdo not ease even with treatment (NIMH, Health and Education, MentalHealth Information as posted on the NIMH Web Site). Not everyone who isdepressed experiences every symptom. Some people experience only a fewsymptoms while others may experience many. For a diagnosis ofdepression, signs and symptoms have to be present most of the day,nearly every day, for at least two weeks (DSM-5).

Depression can happen at any age (NIMH, Health and Education, MentalHealth Information as posted on the NIMH Web Sit), but often begins inadulthood. Depression is now recognized as occurring in children andadolescents, although it sometimes presents with more prominentirritability than low mood. Depression, especially in midlife or olderadults, can co-occur with other serious medical illnesses, such asdiabetes, cancer, heart disease, and Parkinson's disease. Risk factorsinclude: personal or family history of depression; major life changes,trauma, or stress; certain physical illnesses and medications.

Some forms of depression are slightly different, or develop under uniquecircumstances (NIMH, Health and Education, Mental Health Information asposted on the NIMH Web Sit), such as:

Persistent depressive disorder (also called dysthymia), with early orlate onset and with or without atypical features, is a depressed moodthat lasts for at least two years. A person diagnosed with persistentdepressive disorder may have episodes of major depression along withperiods of less severe symptoms, but symptoms must last for two years tobe considered persistent depressive disorder.Perinatal depression is much more serious than the “baby blues”(relatively mild depressive and anxiety symptoms that typically clearwithin two weeks after delivery) that many women experience after givingbirth. Women with perinatal depression experience full-blown majordepression during pregnancy or after delivery (postpartum depression).The feelings of extreme sadness, anxiety, and exhaustion that accompanyperinatal depression may make it difficult for these new mothers tocomplete daily care activities for themselves and/or for their babies.Psychotic depression occurs when a person has severe depression plussome form of psychosis, such as having disturbing false fixed beliefs(delusions) or hearing or seeing upsetting things that others cannothear or see (hallucinations). The psychotic symptoms typically have adepressive “theme,” such as delusions of guilt, poverty, or illness.Seasonal affective disorder is characterized by the onset of depressionduring the winter months, when there is less natural sunlight. Thisdepression generally lifts during spring and summer. Winter depression,typically accompanied by social withdrawal, increased sleep, and weightgain, predictably returns every year in seasonal affective disorder.Mood dysregulation disorder (diagnosed in children and adolescents;DSM-5).

Premenstrual Dysphoric Disorder (PMDD; DSM-5).

Bipolar Disorder is different from depression, but it is included inthis list since patients with bipolar disorder experience episodes ofextremely low moods that meet the criteria for major depression (called“bipolar depression”). Bipolar disorder is a persistent, episodic anddebilitating condition with an estimated lifetime prevalence of over2.0%, including both types I (with mania) and II (with hypomania)(reviewed in Poon et al, 2015). Bipolar disorder is associated withrecurring episodes of mania, hypomania, mixed manic depressive states,or psychosis, as well as prominent major depression and dysthymia, aswell as prevalent anxiety symptoms all leading to high risks ofpotentially severe functional impairment, substance abuse, and highrates of suicide, accidents, and increased mortality from co-occurringmedical illnesses—all despite use of available pharmacological andpsychosocial treatments (Poon et al, 2015). The depressive components ofthe disorder have been especially difficult to treat successfully andthey account for three-quarters of the nearly 50% of weeks of follow-upwith treatment that include clinically significant residual morbidity(reviewed in Poon et al, 2015).

Other mood disorders encompassed within the term “depression” includeAlzheimer's disease with depressed mood, depressed mood in Parkinson'sdisease, Lewy body disease, and other dementias, post-stroke depression,schizoaffective disorders, adjustment disorder with depressed mood, anddrug- and alcohol-induced depressed mood.

Depression is usually initially treated with medications andpsychotherapy. If the treatments do not reduce symptoms,electroconvulsive therapy and other brain stimulation therapies mayhelp. Medications include the following (Mayo Clinic):

Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine(Prozac), paroxetine (Paxil, Pexeva), sertraline (Zoloft), citalopram(Celexa) and escitalopram (Lexapro).Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine(Cymbalta), venlafaxine (Effexor XR), desvenlafaxine (Pristiq, Khedezla)and levomilnacipran (Fetzima).Norepinephrine-dopamine reuptake inhibitors (NDRIs) such as bupropion(Wellbutrin, Aplenzin, Forfivo XL).Atypical antidepressants such as trazodone and mirtazapine (Remeron),vortioxetine (Brintellix), and vilazodone (Viibryd).Tricyclic antidepressants (TCAs) such as imipramine (Tofranil),nortriptyline (Pamelor), amitriptyline, doxepin, trimipramine(Surmontil), desipramine (Norpramin) and protriptyline (Vivactil). Thesecan be very effective, but tend to cause more-severe side effects thannewer antidepressants. Tricyclics are therefore usually considered assecond line therapy.Monoamine oxidase inhibitors (MAOIs), such as tranylcypromine (Parnate),phenelzine (Nardil) and isocarboxazid (Marplan), may be prescribed,typically when other medications haven't worked. However, MAOIs areusually not first line antidepressant therapy, because they can haveserious interactions with certain foods and some medications includingbirth control pills, decongestants and certain herbal supplements.Selegiline TTS (Emsam), a newer MAOI, may cause fewer side effects thanother MAOIs.

One disadvantage of all of the above antidepressant medications is thatthey typically take 2 to 4 weeks to start having an antidepressanteffects.

(S)-6-propyl amino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine(pramipexole) is a synthetic aminothiazole derivative, described in U.S.Pat. No. 4,886,812, the content of which is incorporated herein byreference. It is a dopamine autoreceptor agonist (Schneider and Mierau1987) that is approved for the “treatment of signs and symptoms of earlyParkinson's disease” (herein below referred to as “symptomatic treatmentof PD”), in doses ranging from 0.375 mg/day to 4.5 mg/day, given in 3equally divided doses (Mirapex® Prescribing Information, July 2016).Pramipexole is supplied in tablets for immediate release containing0.125 mg, 0.25 mg, 0.5 mg, 1 mg and 1.5 mg of pramipexoledihydrochloride monohydrate; and in tablets for extended releasecontaining 0.375 mg, 0.75 mg, 1.5 mg, 3 mg and 4.5 mg of pramipexoledihydrochloride monohydrate. It is structurally distinct from theergot-derived drugs (ergoline class, e.g., bromocriptine and pergolide).Pramipexole is a dopamine D2 receptor agonist that is alsopharmacologically unique in that it is a full agonist and has receptorselectivity for the dopamine D3 receptor subtype of the D2 subfamily ofreceptors. These properties may confer advantages in terms of bothefficacy (full agonist with potential for greater therapeutic effects)and safety (receptor selectivity may reduce unwanted side effects)compared to currently available dopamine agonists [Piercey, 1998].

Pramipexole was also found to be effective in the treatment ofdepressive symptoms in patients with PD, albeit with a small effectsize. A 12-week, double-blind, placebo controlled trial in 296 PDpatients was conducted with pramipexole (0.125 to 1.0 mg/kg). Theprimary endpoint was the Beck Depression Inventory scale (BDI). Resultsshowed that BDI scores decreased by an adjusted 5.9 (SE 0.5) in thepramipexole group, and 4.0 (SE 0.5) in the placebo group. The differencebetween the 2 treatment groups was significant (p=0.01; Barone et al.,2010), although the magnitude of the effect size was small. In addition,other small, often open-label studies in which pramipexole was added onto antidepressant treatment (augmentation) also showed modest butsignificant efficacy in favor of pramipexole in non-PD patients withmajor depressive disorder (MDD; Cusin et al., 2013; Goldberg et al,2004), including non-PD patients with treatment resistant depression(Hori and Kunigi, 2012; Pae, et al., 2013; Fawcett et al., 2016), andpatients with depression associated with bipolar disorder (reviewed inSienaert et al., 2013; Dell'Osso and Ketter, 2013; Tondo et al., 2014;et al, 2016). However, Kleebatt et al. (2017) in their review judgedthat clear proof of antidepressant efficacy had not been obtained forpramipexole, and attributed this to low levels of evidence, small samplesizes or discordant results. In all these reports, the dose ofpramipexole remained within the range approved for the treatment of PD,even when the title of the publication mentions “high doses” ofpramipexole (Fawcett et al., 2016). Since in most of these studies,efficacy appeared to be modest, higher doses of pramipexole were testedin a randomized, prospective, double-blind, placebo-controlled,fixed-dose study (Corrigan et al., 2000). A total of 174 eligiblepatients with a DSM-III-R diagnosis of major depression (single orrecurrent episode, with or without melancholia and without psychoticfeatures) were assigned to one of five treatment groups: placebo group,fluoxetine group (20 mg/day), or one of three pramipexole groups (0.375mg/day; 1 mg/day; 5 mg/day). Patients received a 1-week placebo run-in,8 weeks of treatment, and a 1-week post-study follow-up assessment (week9). Efficacy was measured primarily by the change from baseline in theHAM-D (17-item version) total score, MADRS total score, and theCGI-Severity of Illness (SI) score. Results showed that the majority ofpatients in each treatment group completed the study (66-86%), with theexception of the pramipexole 5.0 mg group (45.4%). In the pramipexole5.0 mg group, 57.6% of patients discontinued treatment prematurely,mainly because of adverse events (AEs), 76% of patients reported nausea,and 39% reported vomiting. At endpoint (week 8), the pramipexole 1.0 mggroup and the fluoxetine group showed significantly better improvementover baseline than the placebo group on the HAMD (p=0.0076) and on theMADRS. The pramipexole 5.0 mg group had the best improvement at week 8(−15.00), but p values were not available for this test against placebobecause of the high drop-out rate.

Taken together, the results reported by Corrigan et al. (2000) suggestthat higher doses of pramipexole could be more effective, but doseshigher than the approved doses cannot be used because of a highincidence of dose-limiting adverse events (AEs), notably nausea andvomiting. Also, previously, animal studies suggested that high doses ofpramipexole should be more effective for the treatment of depression.For example, high doses of pramipexole proved to be active in diversetests of animal behavior simulating symptoms of depression, includingWillner's Anhedonia Test (Willner et al., 1994), Fixed Interval Test,Forced Swimming Test, and REM Sleep Inhibition Test.

The present inventors, in a different therapeutic context, disclosed theability to increase the doses of an acetylcholinesterase inhibitor bycombining said acetylcholinesterase inhibitor with an antiemetic agent,including 5HT3-antagonists, in US 2011/0071135.

The document US 2014/0024644 (see also WO 2014/014951 and WO2014/014962) discloses indole and indazole-acetic acid or -acetamidederivatives, esterified or N-substituted with azabicycloalkyl oroxaazabicycloalkyl groups, endowed with a 5HT3-antagonist activity. Thecompounds described therein are asserted to be useful for the treatmentof diseases treatable by inhibition of the 5HT3 receptor. This documentenumerates a series of disorders that may be treated with a5HT3-antagonist: emesis, migraine, substance abuse and addiction,neurodegenerative and psychiatric disorders (including depression),gastrointestinal disorders, immunological disorders, atherosclerosis andinflammation. The document also discloses the possible combination ofsaid 5HT3-antagonists with six classes of neuroleptic agents and with agreat number of active agents including pramipexole. This documentneither mentions nor suggests any possible combination with pramipexolefor the treatment of a MDD.

In conclusion, notwithstanding the massive literature reporting thepossibility of an enhanced pramipexole antidepressant efficacy linked toan increase of the pramipexole dose, in particular the Willner et al1994, Corrigan et al 2000, and US 2011/0071135 disclosures, pramipexoleremains practically inactive in the treatment of depression.

Thus, the problem of providing safe, chronic, effective treatment of apatient suffering from depression with pramipexole is not yet solved.

SUMMARY OF THE INVENTION

The present invention relates to increasing the therapeutic window forpramipexole, for the treatment of depressive disorders such as MDD tosafely enable its full antidepressant efficacy. In particular, thepresent invention relates to a combination of pramipexole with a5HT3-antagonist to increase the therapeutic window for pramipexole.

It has been found that ondansetron or a pharmaceutically acceptable saltor solvate thereof, by reducing or even abrogating the GI side effectsof high doses of pramipexole enables the full antidepressant potentialof pramipexole.

It has also been found that, by using said 5HT3-antagonist, incombination with pramipexole or a pharmaceutically acceptable salt orsolvate thereof, it is possible to safely treat a patient suffering fromdepression by maintaining a therapeutically effective pramipexole dailydose with minimal adverse effect.

The combination of said 5HT3-antagonist with pramipexole or apharmaceutically acceptable salt or solvate thereof enables the fullantidepressant efficacy of pramipexole.

For example in the case of pramipexole dihydrochloride monohydrate, itscombination with said 5HT3-antagonist allows the administration of atherapeutically effective dose of said pramipexole dihydrochloridemonohydrate that, in many patients, significantly exceeds theaforementioned maximum recommended dose (4.5 mg/day) of pramipexoledihydrochloride monohydrate for the treatment of the symptoms of PD,thus increasing its efficacy in the treatment of a patient sufferingfrom a MDD.

More particularly, it has been found that, in patients suffering from adepressive disorder, doses of pramipexole equivalent to a range of from5 mg to 45 mg per dose, or from 5 mg to 45 mg/day, normally from 5 mg to20 mg/day, of pramipexole dihydrochloride monohydrate, in combinationwith a 5HT3-antagonist, offer significant efficacy and a fast onset ofaction. Advantageously, in combination with a 5HT3-antagonist,pramipexole daily doses equivalent to from more than 4.5 mg to 45 mg,from 5 mg to 45 mg, from more than 6 mg to 45 mg or from 6.5 mg to 45mg, normally from more than 6 mg to 20 mg or from 6.5 to 20 mg ofpramipexole dihydrochloride monohydrate provide safe treatment forpatients suffering from MDD.

Hitherto, notwithstanding the aforementioned massive literaturereporting the possibility of pramipexole antidepressant efficacy, no onesuspected that major depressive disorders could be safely cured by usinga pramipexole/5HT3-antagonist combination at the currently usedpramipexole daily doses and also at daily doses higher, and even muchhigher than those recommended for the treatment of PD, and substantiallywithout the inherent pramipexole adverse effects.

Thus, the present invention provides a pharmaceutical combinationcomprising

-   (a) a 5HT3-antagonist; and-   (b) pramipexole or a pharmaceutically acceptable salt or solvate    thereof, in an effective daily dose,    for use for the treatment of depressive disorders such as MDD.

According to a first aspect, the present invention provides the use of(or a method using) a 5HT3-antagonist for enabling the fullantidepressant efficacy of pramipexole in the treatment of MDD.

More precisely, according to this first aspect, the invention provides a5HT3-antagonist, for use in the treatment of a MDD, in combination withan effective daily dose of pramipexole. Said effective pramipexole dailydose may be higher, and even much higher than the maximum daily doserecommended in the treatment of PD.

According to this first aspect, the invention also provides a method fortreating a patient suffering from a major depressive disorder, whichcomprises treating said patient with a 5HT3-antagonist, in combinationwith an effective daily dose of pramipexole or a pharmaceuticallyacceptable salt or solvate thereof. Said effective daily dose (inpramipexole dihydrochloride monohydrate) can significantly and safelyexceed the maximum dose of pramipexole dihydrochloride monohydraterecommended for the symptomatic treatment of PD.

Thus, according to this first aspect, the method (or use) provides thesafe administration of a 5HT3-antagonist in combination with pramipexoledaily doses (in pramipexole dihydrochloride monohydrate) of from 0.375mg to 45 mg. For each patient, after the initial titration starting at adaily dose of 0.375 mg, said daily dose is gradually increased to a doseregiment of from 3 mg to 45 mg, preferably from more than 4.5 mg to 45mg, from 5 mg to 45 mg, from more than 6 mg to 45 mg or from 6.5 mg to45 mg, normally from more than 4.5 mg to 20 mg, from 5 mg to 20 mg, frommore than 6 mg to 20 mg, or from 6.5 mg to 20 mg.

In particular, the invention provides a method (or the use of said5HT3-antagonist) for treating a patient suffering from a majordepressive disorder, which comprises treating said patient with said5HT3-antagonist, in combination with a pramipexole or a pharmaceuticallyacceptable salt or solvate thereof at a daily dose equivalent to frommore than 4.5 mg to 45 mg, preferably from 5 mg to 45 mg, from more than6 mg to 45 mg or from 6.5 mg to 45 mg of pramipexole dihydrochloridemonohydrate.

Normally, as set forth above, said pramipexole daily dose, depending onthe degree of gravity of the illness and the age and condition of thepatient, will be equivalent to from 5 mg to 20 mg from more than 6 mg to20 mg, or from 6.5 mg to 20 mg of pramipexole dihydrochloridemonohydrate.

According to a second aspect, the invention provides the use of said5HT3-antagonist for the preparation of a medicament consisting of apharmaceutical composition comprising, as an active ingredient, said5HT3-antagonist, in admixture with a pharmaceutical carrier or vehicle,for preventing or curing the AEs of pramipexole or of a pharmaceuticallyacceptable salt and/or solvate thereof in the treatment of MDD, andalso, principally, for administering said pramipexole to a patientsuffering from MDD at doses higher, and even much higher than themaximum recommended doses approved for the treatment of PD, thusincreasing the pramipexole efficacy in combating MDD.

In particular, according to this second aspect, the invention providesthe use of a 5HT3-antagonist for the preparation of a medicamentconsisting of a pharmaceutical composition comprising, as an activeingredient, said 5HT3-antagonist, in admixture with a pharmaceuticalcarrier or vehicle, for the treatment of a MDD in combination with aneffective daily dose of pramipexole or a pharmaceutically acceptablesalt or solvate thereof.

Preferably, according to this second aspect, the invention provides theuse of a 5HT3-antagonist for the manufacture of a medicament for thesafe treatment of a MDD, in combination with pramipexole or apharmaceutically acceptable salt or solvate thereof at a daily dose (inpramipexole dihydrochloride monohydrate) that can significantly andsafely exceed the maximum dose of pramipexole dihydrochloridemonohydrate recommended for the symptomatic treatment of Parkinson'sdisease. As described above, said daily dose (in pramipexoledihydrochloride monohydrate) is from 0.375 mg to 45 mg, in particularfrom more than 4.5 mg to 45 mg, from 5 mg to 45 mg, from more than 6 mgto 45 mg or from 6.5 mg to 45 mg, normally from 5 mg to 20 mg, from morethan 6 mg to 20 mg or from 6.5 mg to 20 mg.

According to an embodiment, for said method (or use), said5HT3-antagonist and said pramipexole or pharmaceutically acceptable saltor solvate thereof are each formulated in a pharmaceutical compositionin admixture with a pharmaceutical carrier or vehicle and separatelyadministered, concurrently or sequentially, to the patient in need oftreatment with said combination, in particular to a patient sufferingfrom a MDD. Normally, said compositions are in dosage unit form.

According to another embodiment, for said use or said method, said5HT3-antagonist and said pramipexole or pharmaceutically acceptable saltor solvate thereof are mixed together and formulated in a pharmaceuticalcomposition (fixed-dose combination), in admixture with a pharmaceuticalcarrier or vehicle, to be administered to the patient suffering from aMDD, in need of said treatment. Normally, said compositions are indosage unit form.

A 5HT3-antagonist indicated for the prevention of post-operative nauseaand vomiting or of chemotherapy-induced nausea and vomiting maypreferably be used in combination with a dose of pramipexole that isgenerally currently used for treating PD, or with a higher, and evenmuch higher dose. The use of this combination significantly improves theconditions of patients suffering from a MDD by concurrently mitigatingor even eliminating the pramipexole adverse effects, otherwiseintolerable when using said pramipexole alone.

According to the present invention, preferably, said 5HT3-antagonistsused are those shown to be effective in or approved for the preventionor treatment of postoperative nausea and vomiting or for the preventionof the chemotherapy-induced nausea and vomiting. In fact, surprisingly,5HT3 receptor inhibitors, known to block nausea, vomiting, and diarrheainduced by chemotherapeutic drugs, have been shown, in particular whenadministered at high doses, to also block the gastro-intestinal sideeffects of pramipexole without affecting its efficacy in treating saidMDD.

This finding is surprising because, notwithstanding the gravity of theillnesses and the fact that both said 5HT3-antagonists and pramipexolewere two families of products in use during more than a decade, each inits own indication, to date no one thought that, by combining aneffective dose of said 5HT3-antagonist with an effective dose ofpramipexole, it would be possible to safely improve the conditions ofpatients suffering from a MDD, by also allowing an increase of thepramipexole therapeutic dose, in particular the dose of pramipexoledihydrochloride monohydrate.

According to yet a further embodiment, the invention provides apharmaceutical fixed-dose combination consisting of a pharmaceuticalcomposition comprising an effective dose/unit form of a 5HT3-antagonist,as Component (a) and an effective dose/unit form of pramipexole, asComponent (b), in admixture with a pharmaceutical carrier or vehicle.

In said combination, Component (a) is present in said composition in anamount per unit form of from 1 μg to 300 mg; and Component (b) ispresent in said composition in an amount per unit form equivalent tofrom 0.125 mg to 45 mg, normally from 0.125 mg to 20 mg of pramipexoledihydrochloride monohydrate.

The dose per unit form of pramipexole or pharmaceutically acceptablesalt or solvate thereof, in pramipexole dihydrochloride monohydrate,will normally be in a range selected from the group consisting of from1.5 mg to 20 mg, from 1.625 mg to 20 mg, from 3 mg to 20 mg, from 5 mgto 20 mg, from more than 6 mg to 20 mg and from 6.5 mg to 20 mg.

DETAILED DESCRIPTION

The present invention relates to a pharmaceutical combination comprisinga 5HT3-antagonist, preferably shown effective or indicated for theprevention of post-operative nausea and vomiting or of thechemotherapy-induced nausea and vomiting, for use for the treatment ofMDD in combination with pramipexole; and to the use of a pharmaceuticalcombination comprising said 5HT3-antagonist and pramipexole, for thepreparation of a medicament for treatment of MDD comprising an effectivedose per unit form of pramipexole. Said effective dose may be higher,and even much higher than the pramipexole maximum daily dose recommendedin the treatment of PD.

More particularly, the invention concerns, according to its aspects,

-   -   a method for the treatment of a MDD in a patient in need of said        treatment, which comprises administering to said patient a        5HT3-antagonist in combination with a therapeutically effective        pramipexole daily dose;    -   a 5HT3-antagonist for use for the treatment of a MDD in a        patient in need of said treatment, in combination with a        therapeutically effective daily dose of pramipexole; and    -   the use of a 5HT3-antagonist for the manufacture of a medicament        for the treatment of a MDD in a patient in need of said        treatment, in combination with a therapeutically effective daily        dose of pramipexole.

The invention also provides the use of said 5HT3-antagonist for thepreparation of a medicament for the treatment of MDD in a fixed-dosecombination consisting of a pharmaceutical composition comprising said5HT3-antagonist and said pramipexole.

The 5HT3-Antagonist

Any of the 5HT3-antagonists, especially those shown effective orindicated for the prevention of post-operative nausea and vomiting or ofthe chemotherapy-induced nausea and vomiting may be used in combinationwith a dose of pramipexole that is generally currently used for treatingPD, or with a higher and even much higher dose.

The chronic use of this combination improves the condition of a patientsuffering from a MDD, by concurrently mitigating or even eliminating theadverse effects induced by said pramipexole.

According to the present invention, preferably, said 5HT3-antagonistsused are those approved for preventing nausea and vomiting followingcancer chemotherapy.

A useful 5HT3-antagonist is selected from the group consisting of5-methyl-2-[(4-methyl-1H-imidazol-5-yl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3]indol-1-one(alosetron) and pharmaceutically acceptable salts and solvates thereof,especially its hydrochloride, disclosed in U.S. Pat. No. 5,360,800;(±)-6-chloro,3,4-dihydro-4-methyl-3-oxo-N-(quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide(azasetron) and pharmaceutically acceptable salts and solvates thereof,especially its hydrochloride, disclosed in U.S. Pat. No. 4,892,872;[(1S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] 3,5-dichlorobenzoate(bemesetron, CAS: 40796-97-2);(10R)-10-[(2-methyl-1H-imidazol-1-yl)methyl]-5,6,9,10-tetrahydro-4H-pyrido(3,2,1-jk)carbazol-11-one(cilansetron) and pharmaceutically acceptable salts and solvatesthereof, especially its hydrochloride monohydrate, disclosed in U.S.Pat. No. 4,939,136; (3R)-10-oxo-8-azatricyclo[5.3.1.0³′⁸]undec-5-yl1H-indole-3-carboxylate (dolasetron) and pharmaceutically acceptablesalts and solvates thereof, especially its monomethanesulfonatemonohydrate, disclosed in U.S. Pat. No. 4,906,755;(+)-(R)-8,9-dihydro-10-methyl-7-[(5-methylimidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one(fabesetron) and pharmaceutically acceptable salts and solvates thereof,especially its hydrochloride or maleate, disclosed in U.S. Pat. No.5,141,945;1-methyl-N-((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-indazole-3-carboxamide(granisetron) and pharmaceutically acceptable salts and solvatesthereof, especially its hydrochloride, disclosed in U.S. Pat. No.4,886,808;2,3-dihydro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-oxo-1H-benzimidazole-1-carboxamide(itasetron) and pharmaceutically acceptable salts and solvates thereof,especially its hydrochloride, disclosed in U.S. Pat. No. 5,223,511;1-phenylmethyl-2-(1-piperazinyl)-1H-benzimidazole (lerisetron) andpharmaceutically acceptable salts and solvates thereof, specially itshydrochloride, disclosed in U.S. Pat. No. 5,256,665 and, in atransdermal preparation, in U.S. Pat. No. 6,136,807;6-fluoro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one(lurosetron, CAS 128486-54-4) and pharmaceutically acceptable salts andsolvates thereof, especially its mesylate (GR 87445 N); (±)1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one(ondansetron) and pharmaceutically acceptable salts and solvatesthereof, especially its hydrochloride dihydrate, disclosed in U.S. Pat.No. 4,695,578; (3aS)-2-[(S)-1-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1H-benz[de]isoquinoline(palonosetron) and pharmaceutically acceptable salts and solvatesthereof, especially its hydrochloride, disclosed in U.S. Pat. No.5,202,333;1-methylindol-3-yl)-[(5R)-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl]methanone(ramosetron) and pharmaceutically acceptable salts and solvates thereof,especially its fumarate, disclosed in U.S. Pat. No. 5,344,927;endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3,3-dimethyl-indole-1-carboxamide(3,3-dimethyl-N-1αH,5αH-tropan-3α-yl-1-indolinecarboxamide, ricasetron,CAS 117086-68-7) and pharmaceutically acceptable salts and solvatesthereof, especially its hydrochloride; the(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester of1H-indole-3-carboxylic acid (3-tropanylindole-3-carboxylate,tropisetron) and pharmaceutically acceptable salts and solvates thereof,especially its hydrochloride, disclosed in U.S. Pat. No. 4,789,673; and5-chloro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-1-benzofuran-7-carboxamide(zatosetron) and pharmaceutically acceptable salts and solvates thereof,especially its maleate, disclosed in U.S. Pat. No. 5,563,148; thedisclosures of all the US patents cited in this paragraph beingincorporated herein in their entirety by reference.

Advantageously, said 5HT3-antagonist is selected from the groupconsisting of azasetron and pharmaceutically salts and solvates thereof,dolasetron and pharmaceutically acceptable salts and solvates thereof,granisetron and pharmaceutically salts and solvates thereof, ondansetronand pharmaceutically salts and solvates thereof, palonosetron andpharmaceutically salts and solvates thereof, ramosetron, andpharmaceutically salts and solvates thereof and tropisetron andpharmaceutically salts and solvates thereof.

Illustrative examples of salts of said 5HT3-antagonists and of saidpramipexole include acid addition salts with mineral acids such ashydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid,nitric acid, phosphoric acid and the like or with organic acids such asformic acid, acetic acid, propionic acid, oxalic acid, malonic acid,succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,tartaric acid, citric acid, carbonic acid, methanesulfonic acid,ethanesulfonic acid, aspartic acid, glutamic acid and the like. Thesolvation agent is generally water.

Antagonists of the 5HT3 receptor available for the prevention ortreatment of postoperative nausea and vomiting or for the prevention ofchemotherapy-induced nausea and vomiting are particularly usefulaccording to the present invention. In particular, azasetronhydrochloride, commercially available in 10 mg tablet, and in mg vialsfor intravenous injection; dolasetron monomethanesulfonate monohydrate(also referred to as dolasetron mesylate), commercially available in 200mg maximal dose tablet, and in 12.5 mg/0.625 ml vial; granisetronhydrochloride, commercially available in 2.24 mg maximal dose tablet;ondansetron hydrochloride dihydrate, commercially available in 10 mgmaximal dose tablet and in a 2 mg/ml (in ondansetron base) solutionavailable as a 20 ml multidose vial; palonosetron hydrochloride,commercially available in 0.28 mg/5 mL injection and 0.56 mg capsule andin 0.075 mg/1.5 ml or 0.25 mg/5 ml (in palonosetron base) vials;ramosetron, commercially available in 0.15 mg/ml injection and in 0.1 mgoral tablet; and tropisetron hydrochloride, commercially available in5.64 mg capsules, in 2.256 mg/2 ml vials for intravenous injection, andin 5.64-mg vials for intravenous or subcutaneous injection; areparticularly advantageous 5HT3-antagonists.

According to the present invention, the 5HT3-antagonist is used in apharmaceutical composition comprising, as an active ingredient, said5HT3-antagonist in an amount per unit form of from 1 μg to 300 mg, inadmixture with a pharmaceutical carrier or vehicle, and is administered,in combination with a pramipexole daily dose equivalent to from 0.375 mgto 45 mg, normally from more than 4.5 mg to 45 mg, from 5 mg to 45 mg,from more than 6 mg to 45 mg or from 6.5 mg to 45 mg of pramipexoledihydrochloride monohydrate, to a patient suffering from a MDD.

Thus, for example, an oral pharmaceutical composition according to thepresent invention to be chronically administered in combination withpramipexole may comprise a 5HT3-antagonist selected from the groupconsisting of azasetron and pharmaceutically acceptable salts andsolvates thereof, in an amount per unit form equivalent to from 5 mg to10 mg of azasetron hydrochloride, to be administered at a daily doseequivalent to from 15 mg to 40 mg of azasetron hydrochloride; dolasetronand pharmaceutically acceptable salts and solvates thereof, in an amountper unit form equivalent to from 25 mg to 200 mg of dolasetron mesylate,to be administered at a daily dose equivalent to from 75 mg to 200 mg ofdolasetron mesylate; granisetron and pharmaceutically acceptable saltsand solvates thereof, in an amount per unit form equivalent to from 0.5mg to 2 mg granisetron base, to be administered at a daily doseequivalent to from 1.5 mg to 8 mg of granisetron base; ondansetron andpharmaceutically acceptable salts and solvates thereof, in an amount perunit form equivalent to from 0.5 mg to 16 mg, normally from 2 mg to 8 mgof ondansetron base, to be administered at a daily dose equivalent tofrom 6 mg to 64 mg, normally from 6 mg to 32 mg of ondansetron base;palonosetron and pharmaceutically acceptable salts and solvates thereof,in an amount per unit form equivalent to from 0.25 mg to 0.5 mg ofpalonosetron base, to be administered at a daily dose equivalent to from0.75 mg to 2 mg of palonosetron base; ramosetron and pharmaceuticallyacceptable salts and solvates thereof, in an amount per unit formequivalent to from 0.05 mg to 0.2 mg of ramosetron hydrochloride, to beadministered at a daily dose equivalent to from 0.05 mg to 0.2 mg oframosetron hydrochloride; and tropisetron and pharmaceuticallyacceptable salts and solvates thereof, in an amount per unit formequivalent to from 2.5 mg to 5 mg of tropisetron base, to beadministered at a daily dose equivalent to from 7.5 mg to 20 mg oftropisetron base.

Preferably, said 5HT3-antagonist is selected from the group consistingof azasetron hydrochloride, in an amount per unit form equivalent tofrom 5 mg to 10 mg to be administered at a daily dose equivalent to from15 mg to 40 mg of azasetron hydrochloride; dolasetron mesylate, in anamount per unit form equivalent to from 25 mg to 200 mg of dolasetronmesylate, to be administered at a daily dose equivalent to from 75 mg to200 mg; granisetron hydrochloride, in an amount per unit form equivalentto from 0.5 mg to 2 mg granisetron base, to be administered at a dailydose equivalent to from 1.5 mg to 16 mg, normally of from 2 mg to 8 mg;ondansetron hydrochloride dihydrate, in an amount equivalent to from 0.5mg to 32 mg, normally from 2 mg to 32 mg, from 2 mg to 16 mg or from 2mg to 8 mg ondansetron base, to be administered at a daily doseequivalent to from 6 mg to 64 mg, normally from 6 to 32 mg ofondansetron base; palonosetron hydrochloride, in an amount equivalent tofrom 0.25 mg to 0.5 mg palonosetron base, to be administered at a dailydose equivalent to from 0.75 to 2 mg of palonosetron base; ramosetronhydrochloride, in an amount per unit form of from 0.05 mg to 02 mg, tobe administered at a daily dose of from 0.05 mg to 0.2 mg; andtropisetron hydrochloride, in an amount equivalent to from 2.5 mg to 5mg tropisetron base, to be administered at a daily dose equivalent tofrom 7.5 to 20 mg of tropisetron base.

This composition is destined to be administered to a patient sufferingfrom a MDD, in combination with a pharmaceutical composition in dosageunit form comprising pramipexole or a pharmaceutically acceptable saltor solvate thereof, in an amount per unit form in a range equivalent tofrom 0.125 to 45 mg, preferably from more than 4.5 mg to 45 mg, frommore than 6 mg to 45 mg or from 6.5 mg to 45 mg, normally from 3 mg to20 mg, preferably from more than 5 mg to 20 mg, from more than 6 mg to20 mg or from 6.5 mg to 20 mg of pramipexole dihydrochloridemonohydrate.

The pharmaceutical composition in dosage unit form comprising said5HT3-antagonist as described above may contain another activeingredient, in particular pramipexole, co-formulated with said5HT3-antagonist, in admixture with a pharmaceutical carrier or vehiclein a fixed-dose combination.

The Pramipexole

In the combination of the present invention, the beneficial action ofthe 5HT3-antagonist, counteracting the adverse effects of pramipexole inpatients suffering from a MDD, allows for the safe administration ofpramipexole daily doses otherwise not tolerable in most of said patientseven within the currently approved dose-range (from 0.375 mg to 4.5 mgper day) of pramipexole dihydrochloride monohydrate.

In addition, a 5HT3-antagonist, especially selected among those showneffective or approved for the prevention or treatment of postoperativenausea and vomiting or for the prevention of the chemotherapy-inducednausea and vomiting, renders it possible to safely treat said patientswith daily doses of pramipexole or pharmaceutically acceptable saltthereof equivalent to from more than 4.5 mg to 45 mg, from more than 6mg to 45 mg or from 6.5 mg to 45 mg of pramipexole dihydrochloridedihydrate.

Pharmaceutically acceptable salts of pramipexole are those withinorganic or organic acids such as, but not limited to, hydrochloricacid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid,nitric acid, acetic acid, propionic acid, stearic acid, glycolic acid,oxalic acid, succinic acid, lactic acid, maleic acid, hydroxymaleicacid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbicacid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid,2-acetoxybenzoic acid, methanesulfonic acid, ethanesulfonic acid,2-hydroxyethanesulfonic (isethionic) acid, p-toluenesulfonic acid,2-naphthalenesulfonic acid, 4-amino-benzenesulfonic (sulfanilic) acid,2,6-naphthalenedisulfonic acid, 1,5-naphthalenedisulfonic acid, andpamoic (embonic) acid. The solvation solvent is normally water.

For its administration in combination with the 5HT3-antagonist,pramipexole or a pharmaceutically acceptable salt thereof is formulatedin a pharmaceutical composition in dosage unit form comprising aneffective dose per unit form of said pramipexole or pharmaceuticallyacceptable salt thereof, as an active ingredient, in admixture with apharmaceutical carrier or vehicle. Said active ingredient is formulatedaccording to known technologies for any administration route.

In the case of pramipexole dihydrochloride monohydrate, commerciallyavailable, stable pharmaceutical compositions comprising pramipexoledihydrochloride monohydrate, disclosed in WO 2012/0140604 and in WO2008/122638; and sustained release compositions comprising pramipexoledihydrochloride monohydrate, disclosed in U.S. Pat. No. 8,399,016; maybe useful for the use in combination with a 5HT3-antagonist for thetreatment of a MDD. The contents of these documents are incorporatedherein in their entirety by reference.

In pharmaceutical compositions with a 5HT3-antagonist, the dose per unitform of pramipexole or pharmaceutically acceptable salt or solvatethereof is equivalent to a range selected from the group consisting offrom 0.125 mg to 45 mg, from 3 mg to 45 mg, from more than 4.5 mg to 45mg, from 5 mg to 45 mg, from more than 6 mg to 45 mg and from 6.5 mg to45 mg of pramipexole dihydrochloride monohydrate. Normally, said doseper unit form is equivalent to a range selected from the groupconsisting of from 0.125 mg to 20 mg, from 1.6 mg to 20 mg, from 3 mg to20 mg, from more than 4.5 mg to 20 mg, from 5 mg to 20 mg, from morethan 6 mg to 20 mg and from 6.5 mg to 20 mg of pramipexoledihydrochloride monohydrate.

The dose of pramipexole or pharmaceutically acceptable salt or solvatethereof per IR-unit form will preferably be equivalent to a rangeselected from the group consisting of from 0.125 mg to 22.5 mg, from 3mg to 22.5 mg, from more than 4.5 mg to 22.5 mg, from more than 6 mg to22.5 mg and from 6.5 mg to 22.5 mg, normally in a range selected fromthe group consisting of from 0.125 mg to 10 mg, from 1.5 mg to 10 mg,from 1.625 mg to 10 mg, from 3 mg to 10 mg, from more than 4.5 mg to 10mg, from 5 mg to 10 mg, from more than 6 mg to 10 mg, and from 6.5 mg to10 mg of pramipexole dihydrochloride monohydrate, depending on safetyand tolerability (in combination with the 5HT3-antagonist).

The dose per unit form of pramipexole or pharmaceutically acceptablesalt or solvate thereof in an ER formulation, including slow-releasecompositions and transdermal therapeutic systems such as transdermalpatches, will range from an amount per unit form that is equivalent to arange selected from the group consisting of from 0.375 mg to 45 mg, from1.5 mg to 45 mg, from 3 mg to 45 mg, from more than 4.5 mg to 45 mg,from 5 mg to 45 mg, from more than 6 mg to 45 mg and from 6.5 mg to 45mg, of pramipexole dihydrochloride monohydrate, normally equivalent to arange selected from the group consisting of from 0.375 mg to 45 mg, from1.5 to 20 mg, from 3 mg to 20 mg, from more than 4.5 mg to 20 mg, from 5mg to 20 mg, from more than 6 mg to 20 mg, and from 6.5 mg to 20 mg ofpramipexole dihydrochloride monohydrate, depending on the tolerability(in combination with said 5HT3-antagonist).

As set forth in the Definitions, the above pramipexole doses per unitform include low doses that can be used especially in the case of theinitial titration of the pramipexole daily dose or in the less frequentcase of the use in the treatment of pediatric depressed patients.

If said 5-HT3 antagonist is ondansetron, the dose per unit form (inondansetron base) will range from 8 mg to 32 mg.

If said 5-HT3 antagonist is dolasetron, the dose per unit form (indolasetron mesylate) in combination with pramipexole or pharmaceuticallyacceptable salt thereof, at the above doses/unit form, will range from1.5 mg to 200 mg.

First Aspect of the Invention.

As mentioned above, the present invention provides a pharmaceuticalcombination comprising

-   (a) said 5HT3-antagonist, and-   (b) said pramipexole or a pharmaceutically acceptable salt or    solvate thereof,

at an effective daily dose,

for use for the treatment of MDD.

According to a first aspect, the embodiments of the present inventioninclude

a 5HT3-antagonist, for use for the treatment of a MDD in a patient inneed of said treatment in combination with an effective daily dose ofpramipexole or of a pharmaceutically acceptable salt thereof; and

a method for treating a patient suffering from a MDD, which comprisesadministering to a patient in need of said treatment a 5HT3-antagonistin combination with an effective daily dose of pramipexole or apharmaceutically acceptable salt thereof.

In particular, the present invention provides a method for treating apatient suffering from a major depressive disorder, which comprisestreating said patient with an effective dose of a 5HT3-antagonist incombination with an effective daily dose of pramipexole or apharmaceutically acceptable salt thereof.

Normally, said 5HT3-antagonist is administered at a daily dose of from 1μg to 300 mg, in combination with a pramipexole effective daily dose,including a daily dose for use during the titration period, equivalentto from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate.

As known in the art, in the case of the treatment of patients with drugspotentially inducing severe adverse effects, pramipexole may be used atthe lowest doses (daily from 0.375 mg to less than 3 mg or to less than4.5 mg), in combination with a 5HT3-antagonist, but another advantageprovided by the present invention is an increase in the safe titrationthreshold dose, due to the concomitant presence of said 5HT3-antagonist.

In addition, according to the present invention, the concomitantadministration of a 5HT3-antagonist allows for the administration ofpramipexole daily doses much higher than the pramipexole dihydrochloridemonohydrate maximum daily dose recommended in the treatment of PD.

A 5HT3-antagonist indicated for the prevention of post-operative nauseaand vomiting or of chemotherapy-induced nausea and vomiting may besuccessfully used in combination with pramipexole according to thepresent invention.

In this case, in carrying out the method (or according to the use) ofthe present invention, the daily dose of these 5HT3-antagonists is atleast as high as that preventing or treating nausea and vomiting inpediatric or adult patients undergoing a surgical operation or cancerchemotherapy according to the current protocols for said treatment orprevention.

Normally, in the method (or use) for the treatment of a MDD according tothe present invention, pramipexole or pharmaceutically acceptable saltor solvate thereof, normally in a pharmaceutical composition inadmixture with a pharmaceutical carrier or vehicle, is administered to apatient in need of said treatment at a daily dose that is equivalent tofrom 0.375 mg to 45 mg, from 1.5 mg to 45 mg, from 3 mg to 45 mg, from 5mg to 45 mg, from more than 6 mg to 45 mg and from 6.5 mg to 45 mg ofpramipexole dihydrochloride monohydrate, in some cases from 1.5 mg to 20mg, advantageously from 3 mg to 20 mg, preferably from 5 mg to 20 mg ofpramipexole dihydrochloride monohydrate. In said method (or use)pramipexole is administered to said patient in combination with a5HT3-antagonist.

According to a particular embodiment, in said method (or use), saidpramipexole or pharmaceutically acceptable salt thereof is pramipexoledihydrochloride monohydrate, that is orally administered to said patientat a daily dose of from 1.5 mg to 20 mg, advantageously from 3 mg to 20mg, normally from 5 mg to 20 mg. According to this embodiment, in saidmethod (or use) said pramipexole or pharmaceutically acceptable saltthereof is administered to said patient in combination with said5HT3-antagonist, administered by any administration route.

Preferably, in the method (or use) for treating a MDD in a patientaccording to the present invention,

said 5HT3-antagonist, in said combination, is selected from the groupconsisting of ondansetron or a pharmaceutically acceptable salt thereof,administered at a daily dose equivalent to from 2 mg to 32 mg ofondansetron base, and dolasetron and pharmaceutically acceptable saltsthereof, administered at a daily dose equivalent to from 75 mg to 200 mgof dolasetron mesylate; and

said pramipexole or pharmaceutically acceptable salt thereof isadministered at a daily dose equivalent to from 0.375 mg to 45 mg, inparticular from 1.5 mg to 45 mg, from 3 mg to 45 mg, from 5 mg to 45 mg,from more than 6 mg to 45 mg and from 6.5 mg to 45 mg of pramipexoledihydrochloride monohydrate.

Normally, in said method (or use), said 5HT3-antagonist is ondansetronor a pharmaceutically acceptable salt thereof, at an effective dailydose (in ondansetron) of from 4 mg to 32 mg, administered in combinationwith said pramipexole or a pharmaceutically acceptable salt or solvatethereof, at an effective daily dose (in pramipexole dihydrochloridemonohydrate) of from 1.5 mg to 20 mg, advantageously from 3 mg to 20 mg,preferably from 5 mg to 20 mg.

For their administration for the treatment of MDDs, said pramipexole orpharmaceutically acceptable salt or solvate thereof and said5HT3-antagonist are each formulated in a pharmaceutical composition inadmixture with a pharmaceutical carrier or vehicle. In particular, insaid combination, said 5HT3-antagonist is formulated in a pharmaceuticalcomposition in dosage unit form comprising, as an active ingredient, aneffective amount per unit form of said 5HT3-antagonist in admixture witha pharmaceutical carrier or vehicle; and, respectively, said pramipexoleor a pharmaceutically acceptable salt or solvate thereof is alsoformulated in a pharmaceutical composition in dosage unit formcomprising, as an active ingredient, an effective amount of saidpramipexole or a pharmaceutically acceptable salt or solvate thereof inadmixture with a pharmaceutical carrier or vehicle.

More particularly, in said combination,

said 5HT3-antagonist is formulated in a pharmaceutical composition indosage unit form comprising said 5HT3-antagonist in an amount per unitform of from 0.1 mg to 300 mg, in admixture with a pharmaceuticalcarrier or vehicle; and

said pramipexole or pharmaceutically acceptable salt thereof isformulated in a pharmaceutical composition in dosage unit formcomprising said pramipexole or pharmaceutically acceptable salt thereofin an amount per unit form equivalent to from 0.125 mg to 45 mg ofpramipexole dihydrochloride monohydrate, in admixture with apharmaceutical carrier or vehicle.

Preferably, in said combination said 5HT3-antagonist in said compositionis selected from the group consisting of ondansetron andpharmaceutically acceptable salt or solvate thereof, in an amount perunit form equivalent to from 2 mg to 32 mg of ondansetron base, anddolasetron and pharmaceutically acceptable salt or solvate thereof, inan amount per unit form equivalent to from from 25 mg to 200 mg ofdolasetron mesylate.

Pramipexole is preferably present, in said composition, in an amount perunit form equivalent to from 5 mg to 45 mg or from 6.5 mg to 45 mg,normally from 5 mg to 20 mg or from 6.5 mg to 20 mg of pramipexoledihydrochloride monohydrate.

The pharmaceutical compositions thus obtained are concurrently orsequentially administered to a patient suffering from a MDD.

Said pramipexole or pharmaceutically acceptable salt or solvate thereofand said 5HT3-antagonist may also be formulated together in a fixed-dosecombination consisting of a pharmaceutical composition comprising saidpramipexole or pharmaceutically acceptable salt or solvate thereof andsaid 5HT3-antagonist, in admixture with a pharmaceutical carrier orvehicle.

Normally, in the method (or use) of the present invention, saidcombination is a fixed-dose combination consisting of a pharmaceuticalcomposition in dosage unit form comprising an effective amount per unitform of said 5HT3-antagonist, and an effective amount per unit form ofsaid pramipexole or a pharmaceutically acceptable salt thereof, inadmixture with a pharmaceutical carrier or vehicle.

The fixed-dose combinations assure the safe, concurrent administrationof pramipexole or pharmaceutically acceptable salt or solvate thereofand of the 5HT3-antagonist.

As set forth above, when using a 5HT3-antagonist indicated for theprevention or treatment of postoperative nausea and vomiting or for theprevention of the chemotherapy-induced nausea and vomiting, the amountper unit form of said 5HT3-antagonist is at least as high as thepediatric or adult dose approved for this indication. However, it may beup to 6 times said dose.

In the above fixed-dose combinations, the pramipexole dose/unit form, inpramipexole dihydrochloride monohydrate, is in a range selected from thegroup consisting of from 0.125 mg to 45 mg, from 3 mg to 45 mg, frommore than 4.5 mg to 45 mg, from 5 mg to 45 mg, from more than 6 mg to 45mg and from 6.5 mg to 45 mg. Normally said range is selected from thegroup consisting of from 0.125 mg to 20 mg, from 3 mg to 20 mg, frommore than 4.5 mg to 20 mg, from 5 mg to 20 mg, from more than 6 mg to 20mg, and from 6.5 mg to 20 mg; and the dose/unit form of the5HT3-antagonist ranges from 1 μg to 300 mg.

If the 5HT3-antagonist is ondansetron or a pharmaceutically acceptablesalt or solvate thereof, its dose/unit form (in ondansetron) is from 2mg to 32 mg, normally from 4 mg to 32 mg.

If the 5HT3-antagonist is dolasetron or a pharmaceutically acceptablesalt or solvate thereof, its dose/unit form (in dolasetron mesylate) isfrom 1.5 mg to 200 mg.

If said pramipexole or pharmaceutically acceptable salt thereof ispramipexole dihydrochloride monohydrate, the dose-range per oral IR-unitform, depending on safety and tolerability (in combination with the5HT3-antagonist) is selected from the group consisting 0.125 mg to 22.5mg, from 1.5 mg to 22.5 mg, from 3 mg to 22.5 mg, from more than 4.5 mgto 22.5 mg, from 5 mg to 22.5 mg, from more than 6 mg to 22.5 mg, andfrom 6.5 mg to 22.5 mg, normally from 1.5 mg to 10 mg, from 3 mg to 10mg, from more than 4.5 mg to 10 mg, from 5 mg to 10 mg, from more than 6mg to 10 mg, and from 6.5 mg to 10 mg. If the 5HT3-antagonist isondansetron hydrochloride dihydrate, the ondansetron dose per oral IRunit form, in combination with pramipexole dihydrochloride monohydrate,will be equivalent to from 2 mg to 16 mg, normally from 4 mg to 16 mg ofondansetron base.

The dose/unit form of pramipexole or pharmaceutically acceptable saltthereof, in pramipexole dihydrochloride monohydrate, in an ERformulation, including slow-release compositions and transdermaltherapeutic systems such as transdermal patches, will be in a rangeselected from the group consisting of from 1.5 mg to 45 mg, from 3 mg to45 mg, from more than 4.5 mg to 45 mg, from 5 mg to 45 mg, from morethan 6 mg to 45 mg, and from 6.5 mg to 45 mg, normally from 1.5 mg to 20mg, from 3 mg to 20 mg, from more than 4.5 mg to 20 mg, from 5 mg to 20mg, from more than 6 mg to 20 mg, and from 6.5 mg to 20 mg, depending onthe tolerability (in combination with the 5HT3-antagonist).

If the 5-HT3 antagonist is ondansetron or a pharmaceutically acceptablesalt or solvate thereof, the dose/ER-unit form (in ondansetron) willrange from 8 mg to 32 mg.

If the 5-HT3 antagonist is dolasetron or a pharmaceutically acceptablesalt or solvate thereof, the dose/unit form (in dolasetron mesylate) incombination with pramipexole, at the above doses/unit form, will rangefrom 1.5 mg to 200 mg.

Second Aspect of the Invention.

A second aspect of the present invention provides the use of said5HT3-antagonist for the preparation of a medicament consisting of apharmaceutical composition comprising, as an active ingredient, said5HT3-antagonist, in admixture with a pharmaceutical carrier or vehicle,for the treatment of a MDD in combination with an effective daily doseof pramipexole or a pharmaceutically acceptable salt or solvate thereof.

A first embodiment of this second aspect of the invention provides theuse of said 5HT3-antagonist for the preparation of a medicamentconsisting of a pharmaceutical composition comprising, as an activeingredient, said 5HT3-antagonist, in admixture with a pharmaceuticalcarrier or vehicle, for the treatment of a MDD in combination withpramipexole or a pharmaceutically acceptable salt or solvate thereof,also in a pharmaceutical composition in admixture with a pharmaceuticalcarrier or vehicle.

Said pramipexole daily doses may be much higher than the pramipexoledihydrochloride monohydrate maximum daily dose recommended for thetreatment of symptoms of PD.

A second embodiment of this second aspect provides the use of said5HT3-antagonist for the preparation of a medicament consisting of apharmaceutical composition in dosage unit form comprising an effectivedose per unit form of said 5HT3-antagonist, in admixture with apharmaceutical carrier, for the treatment of a MDD in combination withpramipexole or a pharmaceutically acceptable salt or solvate thereof indoses, in pramipexole dihydrochloride monohydrate, at least as high as adose approved for the symptomatic treatment of PD.

In particular, the 5HT3-antagonist is formulated in a pharmaceuticalcomposition comprising said 5HT3-antagonist in an amount per unit formof from 1 μg to 300 mg, from 0.1 mg to 300 mg or from 1 mg to 300 mg, inadmixture with a pharmaceutical carrier or vehicle.

A preferred 5HT3-antagonist in said pharmaceutical composition, for itsindication for the treatment of a MDD in combination with saidpramipexole, is selected from the group consisting of azasetron andpharmaceutically acceptable salts and solvates thereof, in particularits hydrochloride, in an amount/unit form equivalent to from 5 mg to 10mg of azasetron hydrochloride; dolasetron and pharmaceuticallyacceptable salts and solvates thereof, in particular its mesylatemonohydrate, in an amount/unit form equivalent to from 20 mg to 200 mgof dolasetron mesylate; granisetron and pharmaceutically acceptablesalts and solvates thereof, in particular its hydrochloride, in anamount/unit form equivalent to from 0.5 mg to 2 mg granisetron base;ondansetron and pharmaceutically acceptable salts and solvates thereof,in particular its hydrochloride dihydrate, in an amount/unit formequivalent to from 2 mg to 32 mg, normally from 2 mg to 16 mg ofondansetron base; palonosetron and pharmaceutically acceptable salts andsolvates thereof, in particular its hydrochloride, in an amount/unitform equivalent to from 0.1 mg to 2 mg, normally from 0.25 mg to 0.5 mgpalonosetron base; ramosetron and pharmaceutically acceptable salts andsolvates thereof, in particular its hydrochloride, in an amount/unitform equivalent to from 2.5 μg to 100 μg of ramosetron hydrochloride;and tropisetron and pharmaceutically acceptable salts and solvatesthereof, in particular its hydrochloride, in an amount/unit formequivalent to from 2.5 mg to 5 mg tropisetron base.

Said 5HT3-antagonist in said pharmaceutical composition comprising, asan active ingredient, said 5HT3-antagonist in admixture with apharmaceutical carrier or vehicle, is administered, concurrently orsequentially, in combination with pramipexole, also in a pharmaceuticalcomposition, in admixture with a pharmaceutical carrier or vehicle, forthe treatment of a MDD in a patient in need of said treatment. Saidpharmaceutical compositions and the daily doses are illustrated above,in “The pramipexole” section.

These pharmaceutical compositions, constantly used in combination eachother, for the first time allow the use of pramipexole high doses for asubstantial and efficacious treatment of a patient suffering from a MDD.In fact, a pharmaceutical composition as described according to thissecond aspect of the invention allows for the safe treatment of apatient suffering from a MDD, in combination with a pramipexole dailydose of from 0.375 mg to 45 mg, especially from more than 4.5 mg to 45mg, normally from 5 mg to 45 mg, from more than 6 mg to 45 mg or from6.5 mg to 45 mg, thus alleviating and even resolving the depressivestate of said patients. In certain cases, said pramipexole daily dose isfrom more than 4.5 mg to 20 mg, from 5 mg to 20 mg, from more than 6 mgto 20 mg or from 6.5 mg to 20 mg.

In the treatment of MDD, the 5HT3-antagonist and pramipexole are used incombination and the two active components may be co-administeredsimultaneously or sequentially, or in a fixed dose combination includinga pharmaceutical composition comprising the 5HT3-antagonist and6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine, together inadmixture with a pharmaceutically acceptable carrier or vehicle.

The 5HT3-antagonist and pramipexole can be administered separately ortogether in any conventional oral or parenteral dosage unit form such ascapsule, tablet, powder, cachet, suspension, solution, or transdermaldevice.

In the case of separate (concurrent or sequential) administration ofsaid 5HT3-antagonist, in an effective amount per unit form, and of saidpramipexole, in an effective amount per unit form, each of them can bepackaged in a kit comprising said 5HT3-antagonist, in admixture with apharmaceutical carrier or vehicle, in a container; and said pramipexole,in admixture with a pharmaceutical carrier or vehicle, in another,separate container.

In the case of a concurrent administration, as also set forth above,said 5HT3-antagonist and said pramipexole may be formulated together ina fixed-dose combination consisting of a pharmaceutical composition indosage unit form comprising an effective amount per unit form of said5HT3-antagonist and an effective amount per unit form of saidpramipexole or a pharmaceutically acceptable salt thereof, in admixturewith a pharmaceutical carrier or vehicle.

A third embodiment of this second aspect of the invention provides theuse of said 5HT3-antagonist for the preparation of a medicament for thetreatment of a MDD, said medicament being a fixed-dose combinationconsisting of a pharmaceutical composition comprising, as an activeingredient, said 5HT3-antagonist and, as a second active ingredient,pramipexole or a pharmaceutically acceptable salt or solvate thereof, inadmixture with a pharmaceutical carrier or vehicle.

According to this third embodiment of this second aspect of theinvention, said fixed-dose combination consists of a pharmaceuticalcomposition comprising

-   (a) said 5HT3-antagonist; and-   (b) pramipexole or a pharmaceutically acceptable salt or solvate    thereof, in an amount per unit form (in pramipexole dihydrochloride    monohydrate) at least as high as an amount per unit form approved    for the treatment of PD,    in admixture with a pharmaceutical carrier or vehicle, for use for    the treatment of MDD.

Advantageously, according to this third embodiment of this second aspectof the invention, said fixed-dose combination consists of apharmaceutical composition in dosage unit form comprising

-   (a) said 5HT3-antagonist, in an amount/unit form at least at least    as high as an amount/unit form approved for the prevention of    chemotherapy-induced nausea and vomiting; and-   (b) pramipexole or a pharmaceutically acceptable salt or solvate    thereof, in an amount/unit form (in pramipexole dihydrochloride    monohydrate) at least as high as an amount/unit form approved for    the treatment of PD,    in admixture with a pharmaceutical carrier or vehicle, for the    treatment of MDD.

In general, in the above pharmaceutical composition said 5HT3-antagonistis present in an amount of from 1 μg to 300 mg and said pramipexole ispresent in an amount of from 0.125 mg to 45 mg.

If the 5HT3-antagonist is selected from among those indicated for theprevention or treatment of postoperative nausea and vomiting or for theprevention of the chemotherapy-induced nausea and vomiting, said5HT3-antagonist is present in said composition in an amount/unit form atleast at least as high as an amount/unit form shown to be effective inor approved for the prevention or treatment of postoperative nausea andvomiting or for the prevention of the chemotherapy-induced nausea andvomiting, and up to 6 times said dose. Said 5HT3-antagonists and theiramounts per unit form in pharmaceutical compositions for use in thetreatment of MDD are illustrated in the “The 5HT3-antagonist” section.

In these fixed-dose combinations, the pramipexole dose/unit form, inpramipexole dihydrochloride monohydrate, normally ranges from 0.125 mgto 20 mg, advantageously from 3 mg to 20 mg, preferably from 5 mg to 20mg, from more than 6 mg to 20 mg or from 6.5 mg to 20 mg; and thedose/unit form of the 5HT3-antagonist ranges from 1 μg to 300 mg.

If the 5HT3-antagonist is ondansetron or a pharmaceutically acceptablesalt or solvate thereof, its dose/unit form (in ondansetron) is from 2mg to 32 mg, normally from 4 mg to 32 mg.

If the 5HT3-antagonist is dolasetron or a pharmaceutically acceptablesalt or solvate thereof, its dose/unit form (in dolasetron mesylate) isfrom 1.5 mg to 200 mg.

An advantageous fixed-dose combination consists of a pharmaceuticallycomposition in dosage unit form comprising

-   (a) a 5HT3-antagonist selected from the group consisting of    alosetron or a pharmaceutically acceptable salt or solvate thereof,    in particular its hydrochloride, in an amount/unit dose (in    alosetron) of from 0.25 mg to 2 mg; azasetron or a pharmaceutically    acceptable salt or solvate thereof, in particular its hydrochloride,    in an amount/unit dose of from 5 mg to 10 mg; dolasetron or a    pharmaceutically acceptable salt or solvate thereof, in particular    its mesylate monohydrate, in an amount/unit dose (in dolasetron    mesylate) of from 25 mg to 200 mg; granisetron or a pharmaceutically    acceptable salt or solvate thereof, in particular its hydrochloride,    in an amount/unit dose equivalent to from 0.5 mg to 2 mg granisetron    base; ondansetron or a pharmaceutically acceptable salt or solvate    thereof, in particular its hydrochloride dihydrate, in an    amount/unit dose equivalent to from 2 mg to 32 mg of ondansetron    base; palonosetron or a pharmaceutically acceptable salt or solvate    thereof, in particular its hydrochloride, in an amount/unit dose    equivalent to from 0.25 mg to 0.5 mg palonosetron base; ramosetron    or a pharmaceutically acceptable salt or solvate thereof, in    particular its hydrochloride, in an amount/unit dose of from 50 μg    to 40 mg; and tropisetron or a pharmaceutically acceptable salt or    solvate thereof, in particular its hydrochloride, in an amount/unit    dose equivalent to from 2.5 mg to 5 mg tropisetron base; and-   (b) pramipexole or a pharmaceutically acceptable salt or solvate    thereof, in an amount equivalent to from 0.125 mg to 45 mg,    preferably from 5 mg to 45 mg, from more than 6 mg to 45 mg, or from    6.5 mg to 45 mg, and normally equivalent to a range selected from    the group consisting of from 0.125 mg to 20 mg, from 3 mg to 20 mg,    from more than 4.5 mg to 20 mg, from 5 mg to 20 mg, from more than 6    mg to 20 mg and from 6.5 mg to 20 mg, of pramipexole dihydrochloride    monohydrate,    in admixture with a pharmaceutical carrier or vehicle.

According to an embodiment, said advantageous composition comprises, asactive ingredients,

-   (a) a 5HT3-antagonist selected from the group consisting of    ondansetron or a salt or solvate thereof, in an amount (in    ondansetron base) of from 2 mg to 32 mg; and dolasetron, in an    amount (in dolasetron mesylate) from 25 mg to 200 mg; and-   (b) pramipexole or a pharmaceutically acceptable salt thereof, in an    amount (in pramipexole dihydrochloride monohydrate) of from 0.125 mg    to 45 mg, in admixture with a pharmaceutical carrier or vehicle.

Said advantageous composition preferably comprises, as Component (b)pramipexole or a pharmaceutically acceptable salt thereof, in an amount(in pramipexole dihydrochloride monohydrate) selected from the groupconsisting of from 3 mg to 45 mg, from 5 mg to 45 mg, from more than 6mg to 45 mg, and from 6.5 mg to 45 mg.

A 5HT3-antagonist/pramipexole fixed-dose combination, normally for usein the treatment of MDD, consists of a pharmaceutical compositioncomprising a 5HT3-antagonist selected from the group consisting ofondansetron or a pharmaceutically acceptable salt or solvate thereof, inan amount corresponding to from 2 mg to 32 mg of ondansetron base, asComponent (a); and pramipexole or a pharmaceutically acceptable salt orsolvate thereof, in an amount that is equivalent to from 0.125 mg to 20mg, advantageously from 3 mg to 20 mg, preferably from 5 mg to 20 mg,from more than 6 mg to 20 mg or from 6.5 mg to 20 mg, of pramipexoledihydrochloride monohydrate, as Component (b), in admixture with apharmaceutical carrier or vehicle.

Herein, the pramipexole doses/unit forms include low doses that can beused especially in the case of the titration of the pramipexole dailydose or in the less frequent case of use in the treatment of pediatricdepressed patients.

The Formulations

In the pharmaceutical compositions of the present invention for oral,subcutaneous, intravenous, transdermal or topical administration, theactive ingredients are preferably administered in the form of dosageunits, in admixture with the classic pharmaceutical carriers orvehicles.

The pharmaceutical compositions may be formulated in oral forms such astablets or gelatin capsules wherein the 5HT3-antagonist or pramipexoleor both the active ingredients are in admixture with a carrier orvehicle that may include a diluent, such as cellulose, dextrose,lactose, mannitol, sorbitol or sucrose; a lubricant, such as, acid,calcium or magnesium stearate, polyethylene glycol, silica, or talc; andif needed, a binder such as magnesium aluminum silicate, gelatin,methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone.

Said oral forms may be tablets coated with sucrose or with variouspolymers; or, alternatively, the tablets can be manufactured by usingcarriers such as acrylic and methacrylic acid polymers and copolymers;cellulose derivatives such as hydroxypropylethylcellulose; or otherappropriate materials, to have a prolonged or delayed activity byprogressively releasing a predetermined quantity of 5HT3-antagonist orof pramipexole (or of a pharmaceutically acceptable salt or solvatethereof), or of both the active ingredients. The oral formulations canalso be in form of capsules allowing the extended release thepramipexole (or pharmaceutically acceptable salt or solvate thereof), orof 5HT3-antagonist, or of both the active ingredients.

The pharmaceutical compositions may also be formulated in TTS, such as apatch formulation wherein the active ingredient or the mixture of theactive ingredients may comprise adjuvants such as D-sorbitol, gelatin,kaolin, methyl paraben, polysorbate 80, propylene glycol, propylparaben, povidone, sodium carboxymethylcellulose, sodium polyacrylate,tartaric acid, titanium dioxide, and purified water. A patch formulationmay also contain skin permeability enhancer such as lactate esters(e.g., lauryl lactate), triacetin or diethylene glycol monoethyl ether.

In the above pharmaceutical compositions, the preferred pramipexole orpharmaceutically acceptable salt or solvate thereof active ingredient ispramipexole base or its dihydrochloride monohydrate and the preferred5HT3-antagonist active ingredient is ondansetron base or itshydrochloride dihydrate, or dolasetron base or its mesylate monohydrate.

For the intended use in the treatment of MDDs in combination withpramipexole, the 5HT3-antagonist is formulated in a pharmaceuticalcomposition, wherein said 5HT3-antagonist is in admixture with apharmaceutical carrier or vehicle.

The dosage, i.e. the amount of active ingredient in a single dose to beadministered to the patient, can vary widely depending on the age,weight, and the health condition of the patient. This dosage, in apharmaceutical composition in dosage unit form as illustrated hereinabove, includes the administration of a single dose from 1 μg to 300 mgaccording to the potency of each 5HT3-antagonist and the age of thepatient, and a single dose of pramipexole or a pharmaceuticallyacceptable salt thereof that is equivalent to from 0.125 mg to 45 mg,normally from 0.125 mg to 20 mg, advantageously from 3 mg to 20 mg,preferably from 5 mg to 20 mg or from 6.5 mg to 20 mg of pramipexoledihydrochloride monohydrate, according to the age of the patient, fromone to three times a day by intravenous, subcutaneous, oral, ortranscutaneous administration, according to the strength of the doses ofthe each of the active ingredients. If the 5HT3-antagonist isondansetron hydrochloride dihydrate, said dosage (single dose) rangesfrom 4 mg to 16 mg (in ondansetron base): and, if the pramipexole or apharmaceutically acceptable salt thereof is pramipexole dihydrochloridemonohydrate, said dosage (single dose) ranges from 0.125 mg to 45 mg,from 3 mg to 45 mg, from 5 mg to 45 mg, from more than 6 mg or from 6.5mg to 45 mg, normally from 0.125 mg to 20 mg, advantageously from 3 mgto 20 mg, preferably from 5 mg to 20 mg or from 6.5 mg to 20 mg.

Ondansetron may also be administered via a transdermal drug deliverysystem (TDDS). “Transdermal drug delivery system” provides transdermaldelivery using transdermal drug formulations and transdermal patchesincorporating such transdermal drug formulations. For example, thetransdermal drug delivery system may include a composition in form of apatch, a cream, a gel, a lotion or a paste comprising a 5HT3-antagonist(such as ondansetron). Examples of transdermal formulations may include,but are not limited, to those as described in U.S. Pat. No. 6,562,368, atransdermal gel formulation as described in U.S. Pat. Nos. 7,029,694;7,179,483; 8,241,662 and US 2009/0018190, a transdermal or transmucosalpharmaceutical formulation, that can be utilized for topical ortransdermal application, such that solutions, creams, lotions, sprays,ointment, gels, aerosols and patch drug deliveries as described in WO2005/039531, US2007/022379, US 2010/0216880, US 2014/0037713 and U.S.Pat. No. 8,652,491, a transdermal absorption preparation as described inWO2013/061969 and US 2014/0271796, the disclosures of which are hereinincorporated by reference in their entirety. The transdermal patches mayalso include, but are not limited to, a patch pump having an in-dwellingrigid catheter with flexible features and/or a flexible catheterattachment as described in U.S. Pat. No. 9,782,536, a selectivelyactivatable patch pump as described in U.S. Pat. No. 9,724,462, a patchpump attached to a wireless communication system as described in U.S.Pat. No. 9,623,173, a conformable patch pump as described in U.S. Pat.No. 9,616,171, an infusion pump as described in U.S. Pat. No. 8,915,879,a portable infusion drug delivery as described in U.S. Pat. No.8,480,649, a micropump as described in U.S. Pat. No. 8,282,366, and apatch pump as described in U.S. Pat. No. 7,828,771; the disclosures ofwhich are herein incorporated by reference in their entirety. Othertransdermal patches may include, but are not limited to, a patch inwhich oxybutynin is incorporated in an adhesive agent layer compositioncomprising the acrylic-based polymer as the adhesive base agent, and theacrylic-based polymer is a copolymer of polymethyl methacrylate with apolyacrylate as described in U.S. Pat. No. 8,802,134, a patch consistingof a support layer and of an adhesive agent layer arranged on the atleast one surface of the support layer as described in U.S. Pat. No.8,877,235, a patch using a monoglyceride or a mixture of monoglyceridesof fatty acids as skin permeation-enhancer as described in U.S. Pat.Nos. 5,441,740 and 5,500,222, a patch for using a monoglyceride or amixture of monoglycerides plus a lactate ester as skinpermeation-enhancer as described in U.S. Pat. Nos. 5,686,097; 5,747,065;5,750,137 and 5,900,250, a patch with a non-rate controlling tie layeron the skin-proximal surface of the reservoir, not affecting the drugrelease as described in U.S. Pat. Nos. 5,614,211 and 5,635,203, a patchusing triacetin as permeation enhancer as described in U.S. Pat. Nos.5,212,199, 5,227,169, 5,601,839 and 5,834,010, a patch with a matrixmass in the form of a layer which is self-adhesive, and in which thematrix mass consists of ammonium-group-containing (meth)acrylatecopolymers as described in U.S. Pat. No. 6,555,129, a transdermal patchas described in U.S. Pat. Nos. 6,743,441; 7,081,249; 7,081,250;7,081,251; 7,081,252 and 7,087,241; the disclosures of which are hereinincorporated by reference in their entirety. Preferably, the transdermaldrug delivery system is a patch, a patch pump, an infusion pump, or amicropump.

The pharmaceutical compositions of the present invention are formulatedwith the classic excipients suitable for different ways ofadministration. Particularly advantageous are the formulations in theform of tablets, multi-score tablets, coated tables, orallydisintegrating tablets, extended release tablets, hard or soft capsules,extended-release capsules, patches for transdermal administration,liquid oral solutions, syrups or suspensions in a predetermined unitform, and vials for the intravenous or subcutaneous administration.

Thus, for example, a pharmaceutical composition according to the presentinvention to be chronically administered in combination with pramipexoleor a pharmaceutically acceptable salt or solvate thereof, in an amountper unit dose (in pramipexole dihydrochloride monohydrate) of from 0.125mg to 45 mg, from 3 mg to 45 mg, from 5 mg to 45 mg, from more than 6 mgto 45 mg or from 6.5 mg to 45 mg, normally from 0.125 mg to 20 mg,advantageously from 3 mg to 20 mg, preferably from 5 mg to 20 mg or from6.5 mg to 20 mg, to be administered at a daily dose of from 1.5 mg to 45mg, advantageously from 3 mg to 45 mg, preferably from 5 mg to 45 mg orfrom 6.5 mg to 45 mg, normally from 1.5 mg to 20 mg, advantageously from3 mg to 20 mg, preferably from 5 mg to 20 mg or from 6.5 mg to 20 mg,may comprise alosetron hydrochloride, in an amount/unit dose (inalosetron) of from 0.25 mg to 2 mg to be administered at a daily dose offrom 0.25 mg to 3 mg; azasetron hydrochloride, in an amount/unit dose offrom 5 mg to 10 mg to be administered at a daily dose of from 15 mg to20 mg; dolasetron mesylate monohydrate, in an amount/unit dose (indolasetron mesylate) of from 25 mg to 200 mg to be administered at adaily dose of from 75 mg to 200 mg; granisetron hydrochloride, in anamount/unit dose equivalent to from 0.5 mg to 2 mg granisetron base, tobe administered at a daily dose of from 1.5 mg to 8 mg; ondansetronhydrochloride dihydrate, in an amount/unit dose equivalent to from 2 mgto 8 mg ondansetron base, to be administered at a daily dose of from 6mg to 32 mg; palonosetron hydrochloride, in an amount/unit doseequivalent to from 0.25 mg to 0.5 mg palonosetron base, to beadministered at a daily dose of from 0.75 to 2 mg; ramosetronhydrochloride, in an amount/unit dose of from 50 μg to 20 mg to beadministered at a daily dose of from 75 μg to 40 mg; or tropisetronhydrochloride, in an amount/unit dose equivalent to from 2.5 mg to 5 mgtropisetron base, to be administered at a daily dose of from 7.5 to 20mg.

In the case of pediatric or obese patients, the 5HT3-antagonist dailydose may be decided on the basis of the body weight. Thus, for example,azasetron hydrochloride may be administered at a daily dose of 0.4-0.5mg/kg, dolasetron mesylate may be administered at a daily dose of 9-9.5mg/kg, granisetron hydrochloride may be administered at a daily dose of0.09-0.11 mg/kg, ondansetron hydrochloride dihydrate may be administeredat a daily dose of 0.45-0.55 mg/kg, palonosetron hydrochloride may beadministered at a daily dose of 0.03 mg/kg and tropisetron hydrochloridemay be administered at a daily dose of 0.5-0.6 mg/kg.

Example 1

The ability of the 5HT3-antagonists to prevent the gastro-intestinal(GI) adverse effects (AEs) of pramipexole in humans was tested.

A Phase I study was conducted in subjects receiving a single oral doseof pramipexole dihydrochloride monohydrate (“pramipexole”) with orwithout a single oral dose of ondansetron hydrochloride dihydrate(“ondansetron”). The study was single center, single-blind study.

The objective of the study was to demonstrate that ondansetron couldsafely attenuate the gastro-intestinal side effects of pramipexole givenin doses equivalent or higher than those approved in the treatment ofParkinson's Disease or shown in clinical trials to be effective in thetreatment of depression.

To be enrolled in the study, participants the followinginclusion/exclusion key criteria:

Key Inclusion Criteria

-   1. Male and female subjects aged 20-45 years old both ages included.-   2. Females of childbearing potential must agree to be abstinent or    else use any two of the following medically acceptable forms of    contraception from the Screening Period through 14 days after the    study Exit Visit: condom with spermicidal jelly, diaphragm or    cervical cap with spermicidal jelly, or intrauterine device (IUD). A    female whose male partner has had a vasectomy must agree to use one    additional form of medically acceptable contraception. Subjects must    agree to practice the above birth control methods for 14 days after    the final visit as a safety precaution.-   3. Females of non-childbearing potential, defined as surgically    sterile (status post-hysterectomy, bilateral oophorectomy, or    bilateral tubal ligation) or post-menopausal for at least 12 months,    do not require contraception during the study. The reason must be    documented in the source documents.-   4. Males with female partners of childbearing potential must agree    to use a highly effective, medically acceptable form of    contraception from the Screening Period through 14 days after the    study Exit Visit. Males with female partners of childbearing    potential who themselves are surgically sterile (status post    vasectomy) must agree to use condoms with spermicide over the same    period of time. Male subjects must agree to practice the above birth    control methods for 14 days after the final visit as a safety    precaution.-   5. Subjects must be in good health as determined by their medical    history including personal and family psychiatric history and    results of physical examination, electrocardiogram (ECG), vital    signs, and laboratory tests. A subject with a medical abnormality    may be included only if the investigator or designee considers that    the abnormality will not introduce significant additional risk to    the subject's health or interfere with study objectives. 6. Subjects    must be able to clearly and reliably communicate changes in their    medical condition.-   7. Subjects with a body mass index (BMI) between 19.0 and 32.0 kg/m²    (both inclusive).-   8. Subjects able to swallow multiple pills or capsules    simultaneously.-   9. Subjects must have signed an informed consent form indicating    that they understand the purpose of and procedures required for the    study and are willing to participate in the study and comply with    the study procedures and restrictions.

Key Exclusion Criteria:

The criteria for exclusion of a subject from enrollment in the studywere as follows:

-   1. Any clinically relevant acute or chronic diseases which could    interfere with the subjects' safety during the trial, expose them to    undue risk, or interfere with the study objectives.-   2. History or presence of gastrointestinal, hepatic, or renal    disease or other condition known to interfere with the absorption,    distribution, metabolism or excretion of the study drugs.-   3. History of substance abuse, known drug addiction, or positive    test for drugs of abuse or alcohol.-   4. History of drug or other significant allergy.-   5. Known hypersensitivity to pramipexole, or to ondansetron or    similar serotonin receptor antagonists, or to aprepitant or similar    Substance P/NK1 receptor antagonists.-   5. History of and/or current QT interval prolongation, congenital    long QT syndrome, electrolyte abnormalities (e.g., hypokalemia or    hypomagnesemia), congestive heart failure, bradyarrhythmias or other    medicinal products that lead to QT prolongation or 1st degree AV    block at Screening, Day −1, or pre-dose, ≥450 QTcF for males and    ≥470 QTcF for females.-   7. Treatment with centrally active drugs or antiemetics, within 1    months of study entry.-   8. Tobacco or nicotine users (except subjects who stopped using    tobacco or nicotine 1 year or more before enrollment in the study).-   9. Excessive daily consumption of xanthines containing drinks    (i.e. >500 mg/day of caffeine).-   10. Subjects unwilling to curtail prolonged intensive physical    exercise during the study conduct (from the Screening visit until    the last dose of study drug).-   11. Positive test result for hepatitis B surface antigen, hepatitis    C antibody.-   12. Positive test result for HIV 1 or 2 serology.-   13. Likely to need any medical or dental treatment during the study    period.-   14. Use of any prescription or over-the-counter medication within 14    days prior to admission on Day−1. In addition any medications with    central effects are prohibited for a period equal to 5 times the    drug half-life prior to admission (Day −1), should this period be    longer than 14 days.-   15. Subjects unlikely to co-operate during the study, and/or be    questionably compliant in the opinion of the investigator.-   16. Subjects unable to be contacted in case of an emergency.-   17. Intake of an investigational drug within 30 days of study entry.-   18. Show evidence of suicidal ideation within the last 6 months as    assessed by the C-SSRS (Columbia Suicide Severity Rating Scale) at    Screening.

Following enrollment in the study, participants received singleincreasing oral doses of pramipexole given once daily in the morning(Period 1 of the study). The starting dose of pramipexole was 0.5 mg andthe dose was increased daily by 0.5 mg increments. Once a subject hadreached his/her first intolerable dose (FID-1), upward dose escalationwas discontinued. First intolerable dose (FID) was defined as:

-   -   one (1) episode of vomiting; or    -   Two (2) episodes of retching, or    -   One (1) episode of severe nausea(Grade 3; defined as nausea        interfering with activities of daily living or inadequate oral        caloric or fluid intake; tube feeding, total parenteral        nutrition or hospitalization indicated) lasting more than 1        hour, or    -   Three (3) consecutive episodes at every 4 hour ratings of        moderate nausea (Grade 2; defined as subjectively symptomatic,        but not interfering with activities of daily living), or    -   One (1) episode of moderate diarrhea (Grade 2; defined as 4-6        stools more than at baseline).

When a subject reached FID-1 on pramipexole alone, the subject waswashed out for at least 5 days, and then entered Period 2 of the studyduring which the subject received single daily oral doses of pramipexolestarting at 0.5 mg and titrated upward by 0.5 mg increments, togetherwith oral ondansetron hydrochloride dihydrate (10 mg, equivalent to 8 mgondansetron base) until subjects again reached an intolerable dosedefined as above. The FID on oral pramipexole plus oral ondansetron wasreferred to as FID-2.

If a subject reached FID-2 during Period 2 at the same or lower dosethan FID-1, and providing the investigator judged there were no safetyissues and the subject was consenting, the subject received the samedose of pramipexole as the FID-2 dose together with a higher dose oforal ondansetron hydrochloride dihydrate (20 mg, equivalent to 16 mgondansetron base) on the next day and the protocol specified that saidsubject should continue with the remainder of the dose titration withthe higher dose of oral ondansetron hydrochloride dihydrate (20 mg,equivalent to 16 mg ondansetron base) until they reach the intolerabledose (FID2+). All other provisions of the protocol remained unchanged.Assessments were the same as those planned for the dose escalation day.

On each study day, subjects were followed up for up to 8 hours followingdrug administration for AEs, vital signs, ECGs. In addition, alaboratory panel was taken at screening and at the end of the study.

Three subjects were enrolled in the study. The following Table 1summarizes the demographic characteristics of the subjects.

TABLE 1 Demographic Characteristics of Subjects Enrolled in the StudySubject ID Gender Age (years) Baseline Weight (kg) 1001 (019) Female 4076.4 kg 1005 (027) Female 30 54.8 kg 1006 (001) Male 41 99.1 kg 1007(004) Male 38 64.9 kg 1008 (008) Male 39 81.8 kg

All subjects reached FID-1 (pramipexole alone) during the study. Thedose limiting toxicity was gastro-intestinal adverse events in all 5subjects. For all subjects FID-2 was higher than FID-1. During Period 2of the study, 3 of the 5 subjects tolerated the maximum pramipexole doseallowed by the protocol of 6 mg and therefore these subjects did notreach FID-2 (pramipexole with ondansetron). In other words, concomitantadministration of ondansetron with pramipexole prevented the occurrenceof dose-limiting gastro-intestinal adverse events associated with highdoses of pramipexole. Table 2 lists for each subject the values forFID-1 (on pramipexole alone) and FID-2 (on pramipexole+ondansetron).

TABLE 2 Listing of First Intolerable Doses (FID) values FID-1 FID-2FID-1 Dose Limiting Pramipexole + Subject ID (Pramipexole alone) AdverseEvent Ondansetron 1001 2.5 mg GI issues >6.0 mg 1005 2.0 mg Retching  3.0 mg 1006 0.5 mg Moderate nausea   1.0 mg 1007 4.5 mg Severenausea >6.0 mg 1008 1.5 mg Vomiting >6.0 mg

As shown in the following Table 3, the Maximum Tolerated Dose (MTD)during Period 2 was higher than MTD during Period 1 in all subjects, andin 2 subjects MTD-2 was increased by more than 3-fold.

TABLE 3 Listing of Maximum Tolerated Doses (MTD) Maximal Tolerated DoseMTD-1 Pramipexole + Subject ID (Pramipexole alone) Ondansetron MTD2/MTD11001 2.0 mg >6.0 mg >3.0 1005 1.5 mg   2.5 mg 1.67 1006 NA (nottolerated at   0.5 mg >1.0 0.5 mg) 1007 4.0 mg >6.0 mg >1.5 1008 1.0mg >6.0 mg >6 MTD: Maximum Tolerated Dose

Results showed that the co-administration of ondansetron withpramipexole allowed tolerable increases in the dose of pramipexoleresulting in toleration of higher pramipexole doses than if pramipexolehad been given alone.

In conclusion, the co-administration of oral high doses of ondansetronwith pramipexole prevented the occurrence of gastro-intestinal AEs whenpramipexole was given in doses as high as or higher than the recommendedefficacious dose for the treatment of the symptoms of Parkinson'sdisease.

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1. A method for treating a patient suffering from a major depressivedisorder, which comprises treating said patient with a 5HT3-antagonistin combination with an effective daily dose of pramipexole or apharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein, in said combination, said 5HT3-antagonist is administered at adaily dose of from 1 μg to 300 mg.
 3. The method of claim 1, whereinsaid 5HT3-antagonist is selected from the group consisting of azasetronand pharmaceutically salts and solvates thereof, dolasetron andpharmaceutically acceptable salts and solvates thereof, granisetron andpharmaceutically salts and solvates thereof, ondansetron andpharmaceutically salts and solvates thereof, palonosetron andpharmaceutically salts and solvates thereof, ramosetron, andpharmaceutically salts and solvates thereof; and tropisetron andpharmaceutically salts and solvates thereof.
 4. The method of claim 1,wherein said pramipexole is pramipexole dihydrochloride monohydrate. 5.The method of claim 1, wherein, in said combination, said5HT3-antagonist is selected from the group consisting of ondansetron ora pharmaceutically acceptable salt thereof, administered at a daily doseequivalent to from 2 mg to 32 mg of ondansetron base; and dolasetron andpharmaceutically acceptable salts thereof, administered at a daily doseequivalent to from 75 mg to 200 mg of dolasetron mesylate; and saidpramipexole or pharmaceutically acceptable salt thereof is administeredat a daily dose equivalent to from 0.375 mg to 45 mg of pramipexoledihydrochloride monohydrate.
 6. The method of claim 5, wherein, in saidcombination, said pramipexole or pharmaceutically acceptable saltthereof is administered at a daily dose equivalent to from 1.5 mg to 45mg of pramipexole dihydrochloride monohydrate.
 7. The method of claim 5,wherein, in said combination, said pramipexole or pharmaceuticallyacceptable salt thereof is administered at a daily dose equivalent tofrom 5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
 8. Themethod of claim 5, wherein, in said combination, said pramipexole orpharmaceutically acceptable salt thereof is administered at a daily doseequivalent to from 6.5 mg to 45 mg of pramipexole dihydrochloridemonohydrate.
 9. The method of claim 1, wherein, in said combination,said 5HT3-antagonist and said pramipexole or a pharmaceuticallyacceptable salt or solvate thereof are each formulated in apharmaceutical composition in admixture with a pharmaceutical carrier orvehicle.
 10. The method of claim 1, wherein, in said combination, said5HT3-antagonist is formulated in a pharmaceutical composition in dosageunit form comprising said 5HT3-antagonist in an amount per unit form offrom 0.1 mg to 300 mg, in admixture with a pharmaceutical carrier orvehicle; and said pramipexole or pharmaceutically acceptable saltthereof is formulated in a pharmaceutical composition in dosage unitform comprising said pramipexole or pharmaceutically acceptable saltthereof in an amount per unit form equivalent to from 0.125 mg to 45 mgof pramipexole dihydrochloride monohydrate, in admixture with apharmaceutical carrier or vehicle.
 11. The method of claim 10, whereinsaid 5HT3-antagonist in said composition is selected from the groupconsisting of ondansetron and pharmaceutically acceptable salt orsolvate thereof, in an amount per unit form equivalent to from 2 mg to32 mg of ondansetron base, and dolasetron and pharmaceuticallyacceptable salt or solvate thereof, in an amount per unit formequivalent to from from 25 mg to 200 mg of dolasetron mesylate; and saidpramipexole or pharmaceutically acceptable salt thereof in saidcomposition is present in an amount of from 1.5 mg to 45 mg.
 12. Themethod of claim 11, wherein, in said composition, said pramipexole orpharmaceutically acceptable salt thereof is present in an amount perunit form equivalent to from 5 mg to 45 mg of pramipexoledihydrochloride monohydrate.
 13. The method of claim 11, wherein, insaid composition, said pramipexole or pharmaceutically acceptable saltthereof is present in an amount per unit form equivalent to from 6.5 mgto 45 mg of pramipexole dihydrochloride monohydrate.
 14. The method ofclaim 11, wherein, in said composition, said pramipexole orpharmaceutically acceptable salt thereof is present in an amount perunit form equivalent to from 6.5 mg to 20 mg of pramipexoledihydrochloride monohydrate.
 15. A 5HT3-antagonist for use in thetreatment of major depressive disorders in a patient in need of saidtreatment, in combination with an effective daily dose of pramipexole ora pharmaceutically acceptable salt thereof.
 16. Use of a 5HT3-antagonistfor the preparation of a medicament for the treatment of majordepressive disorders in combination with an effective daily dose ofpramipexole or pharmaceutically acceptable salt thereof.
 17. The use ofclaim 16, wherein, in said combination, said medicament is apharmaceutical composition in dosage unit form comprising an effectiveamount per unit form of said 5HT3-antagonist in admixture with apharmaceutical carrier or vehicle, and said pramipexole orpharmaceutically acceptable salt thereof also is in a pharmaceuticalcomposition in dosage unit form comprising an effective amount per unitform of said pramipexole or pharmaceutically acceptable salt thereof, inadmixture with a pharmaceutical carrier or vehicle.
 18. The use of claim17, wherein said combination is a fixed-dose combination consisting of apharmaceutical composition in dosage unit form comprising an effectiveamount per unit of said 5HT3-antagonist, and an effective amount perunit form of said pramipexole or a pharmaceutically acceptable saltthereof, in admixture with a pharmaceutical carrier or vehicle.